My ongoing and future studies will build upon observations I have made in the past, particularly in the area of BRCA1/2-related cancers. Among families with many cases of breast and ovarian cancer occurring in patterns reminiscent of autosomal dominant Mendelian inheritance, approximately 2/3 have mutations in BRCA1 or BRCA2, two genes identified by positional cloning techniques in 1994 & 1995. Germline mutations occur throughout these large genes and analysis typically requires comprehensive screening of more than 10 kilobases of mRNA encoding sequences. Within the initial set of NCI breast-ovarian cancer families I analyzed, most of the 10 mutation-positive families had a different BRCA1 mutation, but three Ashkenazi Jewish families carried the 185delAG frameshift mutation. This led to our observation that approximately 1% of unselected Ashkenazi Jews carry this mutation. Subsequent studies have confirmed this observation and also determined that another BRCA1 mutation, 5382insC, and a very common mutation in BRCA2, 6174delT, together occur in approximately 1 in 40 Ashkenazi Jews, accounting for approximately 80% of all BRCA1/2 mutations in this population. These observations were an entr into more population-based epidemiologic studies that I have lead. It is possible to rapidly test for the three founder mutations in large numbers of Ashkenazi subjects, and our estimates of the penetrance, or risk of cancer among subjects who carry germline mutations in BRCA1 or BRCA2, were well below prior estimates from multiple-case families. Subsequent studies in both isolated and outbred populations have generally confirmed that the average penetrance for breast cancer is approximately 50% by age 70. One of my highest-priority areas of study is to identify genetic loci that modify the risk of cancer in women who carry these germline mutations. I am collaborating with two groups of investigators in the area of modifier identification, one concentrating on Ashkenazi Jewish women, with the intention of conducting genome-wide single nucleotide polymorphism (SNP) based scans as soon as they are feasible, and the other aimed more at testing candidate susceptibility alleles in a combined group of mutation carriers from several outbred populations. These studies are challenging for a number of reasons, including the difficulty faced in identifying a large and representative group of mutation carriers, particularly elderly female mutation carriers without breast or ovarian cancer. To this end, as co-investigator, I am coordinating mutation testing for a large, prospective study of oophorectomy in women at high genetic risk of ovarian cancer, which targets enrolling approximately 800 BRCA1/2 mutat